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T Cells Attacking Neurons

An autoimmune attack on oligodendrocytes and myelin has long been implicated in the pathogenesis of multiple sclerosis (MS) and related neuroinflammatory diseases. More recent data suggest that T cells that invade the brain during neuroinflammation target neurons as well. Moreover, neuronal damage correlates with the clinical course of MS. Using two-photon microscopy, Nitsch et al. investigated interactions between T cells and living neurons in freshly dissected mouse cortical slices. The authors found that fluorescently labeled T cells that had been stimulated with antigen (but not unstimulated T cells) rapidly entered the brain parenchyma and made contact with neurons. Contact with neuronal cell bodies or proximal dendrites elicited oscillations in neuronal calcium concentration (assessed with the calcium indicator Fluo-4) and eventually led to a sustained and lethal increase in intracellular calcium. T cell invasion and effects on neuronal calcium occurred with T cells targeted against a nonmurine antigen, as well as those targeted against proteolipid protein. The same was true of T cells derived from mice whose major histocompatibility complex (MHC) did not match the MHC of the mice providing the brain slice. Calcium overload could be prevented by either pharmacological block of perforin or of either N-methyl-D-aspartate or α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid-kainate type glutamate receptors, which suggests that glutamate toxicity and direct cytotoxic effects combined to elicit neuronal death.